Basic esters of 2, 3-di (4-alkoxyphenyl)-2-hydroxypropanoic acid



Patented May 6, 1952 UNITED STATES PATENT OFFICE BASIC ESTERSOF--2,3-DI(4'-ALKOXY- PHENYL) 2 HYDROXYPROPANOIC ACID Gino R. Treves,New York, N. Y., assignor to Schieifeiin & Co., New York, N. Y., acorporation of'New' York No Drawing. Application April 28, 1949, SerialNo. 90,276

11 Claims.

in which R, R1 and R2 are alkyl groups'and n is a small whole numbersuch as l, 2, 3, 4, etc. It may be noted that R1 may be substituted ineither or both alkoxyphenyl rings in any unoccupied position. Alkylgroups for R, R1 and R2 may be methyl, ethyl, propyl, butyl, etc., andpreferably those containing a small number of carbon atoms, say 1' to 6carbons. A preferred compound is one in which R,'R1- and R2 are methyland n is equal to 2. Other acid addition salts besides the hydrochlorideare the sulfate, nitrate, phosphate, acetate, etc.

The following examples may illustratethe preparation of the newcompounds. In each 'example, each compound whose name is underlined isproduct resulting from the step or steps. described in the paragraphimmediately following.

. EXAMPLE 1 A. 3- (2 -methyl 4 -anethoxyphenyl) -1 ("amethoxyphenyl)-2-propen-1 -one B. 3-(2-methyZ-. 4 -methowyphenyl) -1-(4-methoxyphenyl)-2,3-epo:vypropan-1-one Ten grams of the product of step A are.dissolved in 100 cc. of a mixture of equal parts of ethanol and acetoneat 40 C. To this Warm solution 7.5 cc. of 4 N sodium hydroxide and 111;cc. of 30% hyldrogen peroxide are added. The mixture is maintained at atemperature between 40 and 50 C. for half an hour. A crystalline mate- 2rial separates which is recrystallized from ethanol. It melts at 61-63'C.

C. 3-(2-methyl-4-methoo:yphenyl) 2 -(4-methoryphenyl)-2-hydro.rypropanoic acid A solution of 9.0 gm. of the product of step Bin 35 cc. of ethanol is refluxed for 3 hours with 10 cc. of 30% sodiumhydroxide solution. The resulting mixture is poured over ice, extractedwith ether, the ether removed, and alkaline solution is then separatedandacidified with hydrochloric acid. The precipitate obtained isfiltered oh and recrystallized from ethanol. It melts at 154-155 C.

D. Hydrochloride of beta-(dimethylamino)ethyl ester of3-(2-methyl-4-methomyphenyl) -2-(4- methoxyphenyl) -2-hydroxypropanoicacid solved in absolute alcohol from which it crystal- It melts at158-160 C.

EXAMPLE 2 E. 3-(4-methoccyphenyl) 1 -(2 -1nethyZ4-methoacyphenyl)-2-p'ropen-1 -one lizes.

To a solution of 12.2 gm. 4-methoxy-2-methylacetophenone and 10.6 gm. of4-methoxybenzaldehyde in 60 cc. of ethanol a solution of 4.5 gm.

of sodium in '75 cc. of ethanol is added. The

mixture is left at. room temperature for 1 hour.

The crystalline material which separates melts F. 3'(4-methoxypheny'l)-1-(2-methyZ-4-methomyphenyl) -2,3-epoxypropan-1-oneTo a. solution-of 19.0 gm. of the product of step E in 150 cc. ethanoland 65 cc. of acetone'at 40 C..,.15- cc. of 4 N solution of sodiumhydroxide and A solution of 14.8 gm. of the product of step F in '75 cc.of ethanol is refluxed with 20 cc. of 30% sodium hydroxide solution for4 hours.

The-

3 mixture is poured in water and filtered. The alkaline solution isacidified with hydrochloric acid, the precipitate that is formed beingthen recrystallized from ethanol. It melts at 150- 152 C.

H. Hydrochloride of beta- (dimethylamz'no) ethyl ester of3-(4-methoxyphenyl) -2-(2-methyZ-4- methomyphenyl) -2-hydroa:ypropanoicacid A solution of 5.3 gm. of the product of step G in 30 cc. of dryisopropyl alcohol is refluxed for 12 hours with 2.2 gm. ofbeta-chloroethyldimethylamine. The solid material which separates isfiltered off and discarded. Isopropyl alcohol is then removed and theresidue extracted repeatedly with anhydrous ether. The solid materialformed is recrystallized from absolute ethanol. It melts at 157-158 C.

EXAMPLE 3 I. 3 (4 methomyphenyl)-1-(3methyZ-4-methoxyphenyl)-2-propen-1-one To a mixture of 17.5 gm. of4-methoxy-3-methylacetophenone and 14.5 gm. of 4-methoxybenzaldehyde in50 cc. of ethanol, a solution of 2.3 gm. of sodium in 50 cc. of ethanolis added. The mixture i left standing for half an hour at roomtemperature, and then the crystalline material which separates isfiltered off and recrystallized from ethanol. It melts at 84-86 C.

J. 3 (4-methoryphenyl)-1-(3-methyl-4-methorg phenyl)-2,3-epoa:ypropan-1-one K. 3(4-methomyphenyl)-2-(3-methyZ-4-methoxyphenyl) -2-hydro.ryp1'opanoicacid A solution of 12.0 gm. of the product of step J in 90 cc. ofethanol is refluxed for 5 hours with 1'7 cc. of sodium hydroxide. Thesolution is cooled and filtered, and the filtrate acidified withhydrochloric acid. The precipitate which is formed is then crystallizedfrom methanol. M. P. 149-150 C.

L. Hydrochloride of beta-(dimethylamino) ethyl ester of3-(4-methoxyphenyl) -2-(3-methyl-4 methoxyphenyl) -2-hydrozcypropanoicacid A solution of 7.5 gm. of the product of step K in cc. of dryisopropyl alcohol and 2.2 gm. of betachloroethyl-dimethylamine arerefluxed for 12 hours. The cooled solution is filtered, the solidmaterial discarded, and the isopropyl alcohol is removed under reducedpressure on a steam bath.

The residue is repeatedly washed with anhydrous ether.

dissolved in absolute ethanol from which it crystallizes. It melts at173-174" C.

The compounds identified as D, H, and L in the above examples weretested for their activity as local anesthetics in the eyes of therabbit, using in each case a concentration of 2% by weight inphysiological saline solution. There was a. re-

The solid material which is formed issponse in each case as follows:with D anesthesia was present in less than 2 minutes and lasted for 60to minutes; with H anesthesia was present in less than 2 minutes andlasted 18 to 55 minutes; with L anesthesia was also present in less than2 minutes and was still detectable after minutes. These compounds didnot exhibit concurrent mydriatic activity and are thus suitable for usewhere the simultaneous or concurrent efiect of anesthesia and mydriasisis undesirable.

Compounds D, H and L may also be obtained in the form of the free baseby treating the acid salt with an alkali such as an aqueous solution ofsodium hydroxide, potassium hydroxide, sodium carbonate, etc. Acid saltsare preferable over the free bases because of their water solubility.

I claim:

1. A compound from the class consisting of dialkylamino alkyl esters of2,3-di(4-alkoxyphenyl) -2-hydroxypropanoic acid having an alkyl group inat least one of the alkoxyphenyl rings and acid addition salts of thesame, said alkyl groups and alkoxy group having from 1 to 6 carbonatoms.

2. Dialkylamino alkyl esters of 2,3-di(4-alkoxy phenyl)-2-hydroxypropanoic acid having an alkyl group in one of thealkoxyphenyl rings, said alkyl groups and alkoxy group having from 1 to6 carbon atoms.

3. An acid addition salt of the compound of claim 2.

4. Beta-(dimethylamino)ethyl ester of 2,3-di- (4-methoxyphenyl) 2-hydroxypropanloic acid having an alkyl group in one of themethoxyphenyl rings, said alkyl group having from 1 to 6 carbon atoms.

5. An acid addition salt of the compound of claim 4.

6. The hydrochloride of claim 4.

7. Beta-(dimethylamino)ethyl ester of 3-(2- methyl--methoxyphenyl) 2-(4-methoxyphenyl) 2-hydroxypropanoic acid.

8. The hydrochloride of beta-(dimethylamino)ethyl ester of3-(2-methyl-4-methoxyphenyl) -2-(4-methoxyphenyl) 2 hydroxypropanoicacid.

9. The hydrochloride of beta-(dimethylamino) ethyl ester of3-(4-methoxyphenyl)-2-(2- methyl-l-methoxyphenyl) 2 -hydroxypropanoicacid.

10. Beta-(dimethylamino)ethyl ester of 3-(4- methoxyphenyl) -2-(3-methyl- 4 -methoxyphenyl) -2-hydroxypropanoic acid.

11. The hydrochloride of beta-(dimethylamino)ethyl ester of3-(4-methoxyphenyl)-2-(3- methyl-4-methoxyphenyl) -2-hydroxy-propanoicacid.

GINO R. TREVES.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS OTHER REFERENCES Burtner et al.: J. A. C. 8., vol.65, p. 263 (1943).

Blicke et al.: J. A. C. 8., vol. 65. pp. 1967-1970

1. A COMPOUND FROM THE CLASS CONSISTING OF DIALKYLAMINO ALKYL ESTERS OF2,3-DI(4-ALKOXYPHENYL) -2-HYDROXYPROPANOIC ACID HAVING AN ALKYL GROUP INAT LEAST ONE OF THE ALKOXYPHENYL RINGS AND ACID ADDITION SALTS OF THESAME, SAID ALKYL GROUPS AND ALKOXY GROUP HAVING FROM 1 TO 6 CARBONATOMS.